Cutaneous Small-Vessel Vasculitis Induced by Escitalopram: A Case-Based Brief Review of the Literature

A 65-year-old male with multiple comorbidities and recently diagnosed with diabetic kidney disease developed upper and lower extremity rash following escitalopram initiation for his depressive mood. Clinical assessment and skin biopsy confirmed cutaneous small-vessel vasculitis (CSVV), prompting drug discontinuation and oral methylprednisolone therapy. The resolution of the rash was achieved within a week. This rare case of CSVV induced by escitalopram highlights the importance of timely recognition and management of drug-induced CSVV and adds to the limited literature on selective serotonin reuptake inhibitor-associated CSVV.


Introduction
Selective Serotonin Reuptake Inhibitors (SSRIs) are the cornerstone of pharmacotherapy for major depressive disorder and a variety of mood disorders.Since their introduction, SSRIs have revolutionized the treatment of these psychiatric conditions due to their efficacy and relatively tolerable side effect profile compared to earlier antidepressants.SSRIs work by selectively inhibiting the reuptake of serotonin into presynaptic neurons, thereby increasing the availability of serotonin in the synaptic cleft and enhancing serotoninergic neurotransmission [1].
Despite their widespread use and general safety, SSRIs are associated with a range of adverse effects that warrant caution.Common side effects include gastrointestinal disturbances, sexual dysfunction, and weight gain, which can impact on patient adherence to therapy [2].Furthermore, SSRIs have been linked to dermatological reactions, such as rash and urticaria, and even rarer conditions like cutaneous small vessel vasculitis (CSVV), toxic epidermal necrolysis and Stevens-Johnson syndrome [3].Herein, we report a clinical case of CSVV induced by escitalopram administration.

Case Presentation
A 65-year old man presented at the nephrology outpatient department of this hospital complaining about a rash on both upper and lower extremities developed two days ago.Ten days before presentation, the patient consulted a psychiatrist due to his depressed mood, following the diagnosis of diabetic kidney disease he had received six months earlier.They agreed on cognitive behavioral therapy in combination with escitalopram pharmacotherapy.Other notable medical history included coronary artery bypass graft surgery following an episode of acute myocardial infarction twenty years ago as well as coronary angioplasty seven years ago, type II diabetes mellitus, hypertension, heart failure with mid-range ejection fraction, peripheral artery disease, benign prostatic hyperplasia, hyperuricemia and non-alcoholic fatty liver disease.His medications included rosuvastatin, furosemide, valsartan, carvedilol, amlodipine, empagliflozin, sitagliptin, insuline glargine, febuxostat, aspirin, omeprazole and alprazolam.
At presentation, the man was anxious and concerned about the rash (Figure 1).There was neither pruritus nor pain but clusters of small, slightly elevated red spots typical of palpable purpura.A dermatologist was consulted and a complete panel of lab tests and a skin biopsy were ordered.The rest of a detailed physical examination was unremarkable.Cutaneous Small-Vessel Vasculitis was considered to be our working diagnosis.Escitalopram was withheld and a short, tapered course of oral methylprednisolone was administered for ten days.The patient's anxiety was quelled by explaining the benign nature of this condition.

FIGURE 1: Small-Vessel Cutaneous Vasculitis: confluent petechiae rash presented as clusters of small, slightly elevated red spots typical of palpable purpura on both upper and lower extremities of a 65-years-old man after SSRIs administration
In the follow-up one week after the initial examination, the lesions had completely resolved.Furthermore, escitalopram was replaced by fluoxetine according to the suggestions of the patient's psychiatrist.The results of the skin biopsy revealed the infiltration with polymorphonuclear neutrophils in and around the vessel walls accompanied with signs of activation and death of neutrophils illustrated by abundant nuclear debris (leukocytoclasia); evidence of tissue damage included also the presence of endothelial edema, extravasated erythrocytes, and coexistence of eosinophilic and lymphocytic infiltrates as well as fibrinoid necrosis (Figure 2).Laboratory and imaging results including immunological tests, markers of inflammation, virological and bacteriological testing, repeated microscopic examination of the urine and computed tomography evaluation were unnoteworthy.More results are shown in Table 1.Therefore, by excluding other possible causes of systemic disease, we established this skin-isolated small vessel vasculitis induced by escitalopram as the final diagnosis.

Discussion
Vasculitides encompass a heterogeneous group of disorders characterized by inflammation of blood vessels.These conditions can affect vessels of all sizes and can involve multiple organ systems, manifesting with a variety of clinical presentations ranging from mild skin lesions to life-threatening illness.Etiologically, vasculitides may be idiopathic, infectious, or associated with systemic diseases such as an autoimmune disease, hematological disorder or even malignancy.Pathogenesis often involves immune complex deposition, autoantibodies and aberrant immune response, resulting in vessel wall inflammation.Diagnostic approaches include serological testing, imaging, and histopathological examination of the affected tissues.Management strategies are tailor-made to the specific type of vasculitis, typically involving immunosuppressive therapy to mitigate inflammation and prevent target organ damage [4,5].
Cutaneous small vessel vasculitis (CSVV) is a specific type of vascular inflammation limited to the capillaries, venules and arterioles of the skin.It is usually a diagnosis of exclusion (Table 2).It is of paramount clinical importance that other systemic causes are ruled out.In its drug-induced type, patients develop lesions within 7 to 21 days after their treatment begins.It is considered to be a benign condition, which mostly resolves spontaneously after one single episode.Nevertheless, severe cases may warrant systemic corticosteroid administration.Histopathologically, CSVV is characterized by leukocytoclastic vasculitis, where neutrophils and eosinophils infiltrates are evident within and around the vessel wall; fibrinoid necrosis is also present inside or within the vessel walls.There may be evidence of endothelial damage such as endothelial swelling, sloughing and necrosis, extravasated red blood cells and abundant perivascular nuclear dust due to neutrophil activation and cell death.Immunofluorescence studies, if needed, typically reveal perivascular deposition of immunoglobulins and complement components [4,6].In the majority of CSVV cases the above characteristic lesions are located around the small venules of the upper dermis while the presence of tissue eosinophilia is usually correlated with a drug-induced etiology as observed in our case [7].Management of CSVV focuses on addressing the underlying cause when identifiable.In our case, withdrawal of the offending drug in conjunction with methylprednisolone led to the rapid resolution of the rash.

Table 2. Causes of Cutaneous Small Vessels Vaculitis
To the best of our knowledge, only a few cases of SSRI-induced CSVV have been reported.By scrutinizing the available bibliography, we have found a subset of cases similar to ours but none involving escitalopram.
In the family of the SSRI's, sertraline [8] and paroxetine [9] have been linked with CSVV while fluoxetine has been reported to induce another form of vasculitis, urticarial vasculitis [10].Moreover, in the spectrum of antidepressant drugs, maprotiline [11], a tricyclic antidepressant, sibutramine [12], a serotoninnorepinephrine reuptake inhibitor and vortioxetin, a serotonin modulator and stimulator, were involved in cases of CSVV.Regardless of the causative medication, this rare case underscores the importance of recognizing this adverse drug reaction so that the clinician proceeds to its prompt discontinuation [13].

Conclusions
In conclusion, this case highlights the rare occurrence of CSVV induced by escitalopram, adding to the scant literature of SSRI-induced CSVV.Although it is generally considered benign and self-resolving, some cases may necessitate systemic corticosteroid therapy.Prompt recognition and discontinuation of the offending drug are crucial in managing this adverse drug reaction.Of note, since almost every type of vasculitis may involve the skin, even as their first target organ manifestation, it is of imperative importance to go the long way of exclusion before establishing the diagnosis of CSVV.Last but not least, clinicians should remain vigilant for such clinical presentations, ensuring individualized management to optimize patient outcomes.

TABLE 2 : Causes of Cutaneous Small Vessels Vaculitis Clinically
, patients present with palpable purpura predominantly on the lower extremities although constitutional symptoms, including fever, arthralgia, and malaise may be present.A thorough history and physical examination, supplemented by laboratory tests and skin biopsy, are essential for accurate diagnosis.